This is a second year summary of a 3 year grant designed to investigate the biochemical modulation that occurs in cellular nucleotide metabolism following antimetabolite therapy. Previous work supported by this grant has identified that Pyrazofurin, an inhibitor of orotidylate decarboxylase, will result in a diminution in UTP and CTP pools. Consequently, the analogue of Cytidine, 5-Azacytidine, is rapidly metabolized to toxic nucleotide derivatives. Thymidine in mM dose ranges will augment Ara-C metabolism and cytotoxicity. Current work is designed to investigate the intracellular perturbations that result from various pyrimidine inhibitors (PALA, FdUrd) and then exploit these changes in designing sequence studies with nucleoside analogues.